A 50-year-old man who was receiving amiodarone therapy for
ventricular tachycardia presented to the emergency department following
2 syncopal episodes. A chest radiograph was obtained (Figure 1), and
based on these findings, high-resolution CT (HRCT) of the chest was
performed (Figure 2).

IMAGING FINDINGS

The chest radiograph showed nonspecific bibasilar reticular opacities (Figure 1), which were new since the previous radiograph 1
year earlier (not shown). High-resolution CT showed extensive
interlobular and intralobular interstitial thickening superimposed on
diffuse ground-glass opacities (the "crazy-paving" pattern),
primarily in volving the middle and lower lungs (Figure 2, A through C).
There was also relatively high attenuation of the hepatic parenchyma as
compared with the spleen (Figure 2D).

Transbronchial biopsy of the right lower lobe revealed pulmonary
fibrosis, hemosiderin-laden macrophages, and scattered "foamy"
macrophages with clear cytoplasm. No granulomatous inflammation was
identified. A clinical diagnosis of amiodarone pulmonary toxicity was
made, and the drug was discontinued after a cardiac defibrillator was
implanted.

DIAGNOSIS

Endogenous lipoid pneumonia resulting from amiodarone toxicity

[FIGURE 1 OMITTED]

DISCUSSION

Amiodarone has been used for >30 years for various cardiac
disorders, particularly in treating life-threatening cardiac
dysrhythmias. (1-4) Various ad verse effects involving the nervous
system, gastrointestinal system, eyes, skin, thyroid, and liver are well
known. (1) Pulmonary toxicity, first recognized in 1980, (5) is the most
severe complication. It is estimated that 5% to 10% of patients treated
with amiodarone will develop amiodarone pulmonary toxicity, and 5% to
10% of those affected will die from subsequent respiratory
complications. (2,4,6) Pulmonary toxicity may be mild and reversible or
may progress to fibrosis and, ultimately, may be fatal. In most cases,
it occurs months after therapy is begun, typically with doses of
[greater than or equal to]400 mg per day, although several cases of
toxicity developing after 48 hours of intravenous therapy have been
reported in patients with acute respiratory distress syndrome who were
treated for tachydysrhythmias. Presumably, the alveolar damage leads to
impaired surfactant metabolism and makes amiodorone clearance more
difficult. (7,8)

[FIGURE 2 OMITTED

Pharmacologically, amiodarone has high lipid solubility, a large
volume of distribution, and an elimination half-life ranging from 40 to
60 days. Thus, not only does the drug have the potential to accumulate
in the lung in large quantities, but also, because of extremely slow
elimination, lung injury may persist or progress despite cessation of
therapy. (4)

The initial underlying pathologic process in the lung from
amiodarone toxicity is postulated to be a drug-induced phospholipidosis,
(9) and the mechanism by which phospholipids accumulate in the cell is
believed to be by inhibition of intracellular phospholipase when the
drug and its metabolites are trapped in alveolar macrophages and type II
pneumocyte lysosomes. (4) This is speculated to lead to inhibition of
lipid degradation and surfactant turnover, a mechanism similarly
implicated in pulmonary alveolar proteinosis. (10) Alternatively, a
hypersensitivity response to the drug may develop, resulting in indirect
lung injury. (3)

On light microscopy, characteristic macrophages with foamy and pale
cytoplasm are seen. When interstitial pneumonia is present, nonspecific
interstitial pneumonia is the most common pattern identified. Diffuse
alveolar damage and bronchiolitis obliterans organizing pneumonia have
also been described. (1,9) Areas of fibrosis and hemorrhage can occur as
well. In a patient developing signs and symptoms of drug toxicity, the
presence of these various histologic abnormalities is highly suggestive
of drug toxicity. (9)

Radiographic findings of amiodarone pulmonary toxicity typically
include bilateral, sometimes asymmetric, patchy opacities. (1,3) CT may
show homogeneous peripheral and high-attenuation opacities due to
incorporation of iodine-rich amiodarone (37% iodine by weight) and its
metabolite desethylamiodarone in type II pneumocytes and alveolar
macrophages. (6) Only a limited number of pathologic processes are known
to result in high-attenuation pulmonary parenchymal abnormalities on CT,
including metastatic pulmonary calcifications from secondary
hyperparathyroidism in the setting of renal failure, amyloid deposition,
and diffuse pulmonary ossification. Besides in the lung, amiodarone can
also accumulate in the liver, spleen, and myocardium, causing increased
attenuation in these tissues on unenhanced CT. Patients who have
pulmonary toxicity almost always have increased liver attenuation, a
finding that can help clarify the diagnosis given that the pattern of
pulmonary parenchymal abnormalities can vary.

In some cases of amiodarone pulmonary toxicity, the accumulation of
phospholipids in alveolar macrophages and in other parenchymal cells
leads to lipoid pneumonia. (7) On HRCT, lipoid pneumonia may show
crazy-paving, a colorful description of patchy interlobular and
intralobular septal thickening and ground-glass opacity that may also be
seen with other diseases, including pulmonary alveolar proteinosis, lung
edema, Pneumocystis jiroveci pneumonia, and bronchioloalveolar
carcinoma. The diagnosis of drug-related pulmonary toxicity is often
made based on a combination of clinical and imaging findings with little
or no pathologic confirmation given that empirically discontinuing a
particular drug may be safer than open or transbronchial lung biopsy.
The radiographic and histologic patterns of drug-induced lung injury are
nonspecific, so these findings must be interpreted in the context of
detailed clinical information.

CONCLUSION

Amiodarone, while a highly effective antidysrhythmic, has the
potential to cause severe pulmonary toxicity, ranging from mild,
reversible injury to pulmonary fibrosis. The underlying mechanism is
believed to be related to both amiodarone's large volume of
distribution, long tissue half-life, and its interference with the
normal lipid degradation pathways in the alveolar macrophages and other
pulmonary parenchymal cells. Although the imaging findings may be
nonspecific, the constellation of clinical history with the described
imaging characteristics and amiodarone deposition in other tissues
should alert the radiologist that toxicity from this drug may likely be
the source of the patient's respiratory dysfunction.